The prognostic value of global histone acetylation in cancer was first described by our group and has been since validated independently by multiple other laboratories. These reports have discovered that in cancer tissue, a lower global level of histone acetylation is significantly associated with cancer-related mortality and morbidity. However, the function and regulation of global changes in histone acetylation and its relevance to cancer biology had been completely unknown. Recently, our group has revealed a novel role of chromatin and global histone acetylation as a regulator of intracellular proton load. We have shown that global histone deacetylation is coupled to the co-transport of acetate ions and protons out of the cell through the monocarboxylate transporters (MCTs), allowing for regulation of intracellular pH in acidic conditions. Conversely, histones are globally acetylated at alkaline pH to combat the increase in intracellular pH by sequestering acetate ions from co-transport out of the cell with available intracellular protons. Global deacetylation of histones at low pH requires continuous histone deacetylase (HDAC) activity as pharmacological inhibition of HDACs compromises pHi maintenance in acidic microenvironments. This proposal aims to determine the precise genome-wide distribution of changes in histone acetylation in response to changes in intracellular pH and the consequences for gene expression and cancer cell behavior. We will seek to elucidate the mechanism of pH-induced histone deacetylation and identify the main HDACs involved in regulating this process. Our data thus far suggest the implication of this novel function of global histone acetylation in cancer tissues. We postulate that cancer tissues displaying low histone acetylation levels, may be utilizing this mechanism to maintain a relatively alkaline pHi despite an acidic extracellular environment-a well-known hallmark of rapidly dividing cells. The findings of this research will reveal a novel dimension of chromatin biology and histone acetylation in integrating control of gene expression with cellular physiology. Furthermore, our work will provide new insight into more effective use of HDAC inhibitors (HDACi) in the clinic and has the potential to shine light on mechanisms of HDACi innate and acquired resistance in various types of cancer.